Method of making (S)-3-(aminomethyl)-5-methylhexanoic acid

ABSTRACT

A method of making (±)-3-(aminomethyl)-5-methylhexanoic acid that comprises condensing isovaleraldehyde with ##STR1## to form primarily ##STR2## reacting the ##STR3## with a cyanide source to form ##STR4## decarboxylating the ##STR5## to form ##STR6## hydrolyzing the ##STR7## with an alkali or alkaline earth metal hydroxide to form an alkali or alkaline earth metal carboxylate salt; and hydrogenating the alkali or alkaline earth metal carboxylate salt to form (±)-3-(aminomethyl)-5-methylhexanoic acid, wherein R 1  and R 2  are the same or different and are hydrogen, C 1  -C 6  alkyl, aryl, benzyl, or C 3  -C 6  cycloalkyl. The present invention also provides a method of making (±)-3-(aminomethyl)-5-methylhexanoic acid that comprises condensing isovaleraldehyde with ##STR8## to form primarily ##STR9## reacting the ##STR10## with a cyanide source to form ##STR11## decarboxylating the ##STR12## to form an alkali or alkaline earth metal carboxylate salt; and hydrogenating the alkali or alkaline earth metal carboxylate salt to form (±)-3-(aminomethyl)-5-methylhexanoic acid.

FIELD OF THE INVENTION

This invention relates to a method of making(±)-3-(aminomethyl)-5-methylhexanoic acid and to a method of obtaining(S)-3-(aminomethyl)-5-methylhexanoic acid from(±)-3-(aminomethyl)-5-methylhexanoic acid.

BACKGROUND OF THE INVENTION

3-(Aminomethyl)-5-methylhexanoic acid, which is also calledβ-isobutyl-γ-aminobutyric acid or isobutyl-GABA, is a potentanticonvulsant. Isobutyl-GABA is related to the endogenous inhibitoryneurotransmitter γ-aminobutyric acid or GABA, which is involved in theregulation of brain neuronal activity.

It is thought that convulsions can be controlled by controlling themetabolism of the neurotransmitter γ-aminobutyric acid. When theconcentration of GABA diminishes below a threshold level in the brain,convulsions result (Karlsson A., et al., Biochem, Pharmacol.,1974;23:3053-3061), and when the GABA level rises in the brain duringconvulsions, the seizures terminate (Hayashi T., Physiol, (London),1959;145:570-578). The term "seizure" means excessive unsynchronizedneuronal activity that disrupts normal function.

Because of the importance of GABA as an inhibitory neurotransmitter, andits effect on convulsive states and other motor dysfunctions, a varietyof approaches have been taken to increase the concentration of GABA inthe brain. In one approach, compounds that activate L-glutamic aciddecarboxylase (GAD) have been used to increase concentrations of GABA,as the concentrations of GAD and GABA vary in parallel and increased GADconcentrations result in increased GABA concentrations (Janssens deVarebeke P., et al., Biochem. Pharmacol., 1983;32:2751-2755; Loscher W.,Biochem. Pharmacol., 1982;31:837-842; Phillips N., et al., Biochem.Pharmacol., 1982;31:2257-2261). For example, the compound(±)-3-(aminomethyl)-5-methylhexanoic acid, a GAD activator, has theability to suppress seizures while avoiding the undesirable side effectof ataxia.

It has been discovered that the anticonvulsant effect of isobutyl-GABAis stereoselective. That is, the S-stereoisomer of isobutyl-GABA showsbetter anticonvulsant activity than the R-stereoisomer. See, forexample, Yuen, et al., in Bioorganic & Medicinal Chemistry Letters,1994;4(6):823-826. Thus, it would be beneficial to have an efficientprocess for the synthesis of the S-stereoisomer of isobutyl-GABA.

Presently, (S)-3-(aminomethyl)-5-methylhexanoic acid has been preparedby two synthetic routes. These routes each use reactions that requiren-butyllithium, and both routes contain a step that must be carried outat low temperatures (≦-35° C.) under carefully controlled conditions.These synthetic routes include the use of(4R,5S)-4-methyl-5-phenyl-2-oxazolidinone as a chiral auxiliary tointroduce the stereochemical configuration needed in the final product.See, for example, U.S. Ser. No. 08/064,285, which is hereby incorporatedby reference. Although these routes provide the target compound in highenantiomeric purity, they are difficult to conduct on large-scale anduse expensive reagents which are difficult to handle.

In addition, (±)-isobutyl GABA can be synthesized in accordance withAndruszkiewicz, et al., Synthesis, 1989;953. The synthesis describedtherein uses potentially unstable nitro compounds, includingnitromethane, and an intermediate containing a nitro functional group,which is reduced to an amine in a potentially exothermic and hazardousreaction. The synthesis also uses lithium bis(trimethylsilylamide) at-78° C. The present method does not use nitro compounds, require lowtemperatures, or require strongly basic conditions.

The present invention provides an efficient synthesis of isobutyl-GABAand provides for the resolution of racemic isobutyl-GABA to obtain theS-stereoisomer of isobutyl GABA that avoids the above-identifiedproblems.

SUMMARY OF THE INVENTION

The present invention provides the compounds ##STR13## where R₁ and R₂are the same or different and are hydrogen, C₁ -C₆ alkyl, aryl, benzylor C₃ -C₆ cycloalkyl; ##STR14## where M is hydrogen, an alkali metal, oran alkaline earth metal; ##STR15## where R₁ is defined above; ##STR16##

The present invention provides a method of making(±)-3-(aminomethyl)-5-methylhexanoic acid which comprises condensingisovaleraldehyde with ##STR17## to form primarily ##STR18## reacting the##STR19## with a cyanide source to form ##STR20## decarboxylating the##STR21## to form ##STR22## hydrolyzing the ##STR23## with an alkali oralkaline earth metal hydroxide to form an alkali or alkaline earth metalcarboxylate salt; and hydrogenating the alkali or alkaline earth metalcarboxylate salt to form (±)-3-(aminomethyl)-5-methylhexanoic acid,wherein R₁ and R₂ are the same or different and are hydrogen, C₁ -C₆alkyl, aryl, benzyl, or C₃ -C₆ cycloalkyl.

A preferred method of making (±)-3-(aminomethyl)-5-methylhexanoic acidcomprises condensing isovaleraldehyde with ##STR24## to form primarily##STR25## reacting the ##STR26## with a cyanide source to form ##STR27##decarboxylating the ##STR28## to form an alkali or alkaline earth metalcarboxylate salt; and hydrogenating the alkali or alkaline earth metalcarboxylate salt to form (±)-3-(aminomethyl)-5-methylhexanoic acid.

The present invention also provides a method for obtaining(S)-3-(aminomethyl)-5-methylhexanoic acid from(±)-3-(aminomethyl)-5-methylhexanoic acid which comprises combining(±)-3-(aminomethyl)-5-methylhexanoic acid and (S)-mandelic acid inwater, an alcohol or a mixture of water and an alcohol; allowing aprecipitate to form; introducing the precipitate into a polar aproticsolvent or a mixture of polar aprotic solvent and water to form aslurry; and collecting the solid from the slurry.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with Scheme I below, the present invention provides anefficient synthesis of racemic isobutyl-GABA and a method for obtaining(S)-isobutyl-GABA from racemic isobutyl-GABA. ##STR29## wherein R₁ andR₂ are the same or different and are hydrogen, C₁ -C₆ alkyl, aryl,benzyl or C₃ -C₆ cycloalkyl; and M is hydrogen, an alkali metal, or analkaline earth metal.

Scheme I illustrates a method of making(±)-3-(aminomethyl)-5-methylhexanoic acid (VII or racemic3-(aminomethyl)-5-methylhexanoic acid), the method comprising condensingisovaleraldehyde (I) with (II) to form (III); reacting (III) with acyanide source to form (IV); decarboxylating (IV) to form (V);hydrolyzing (V) with an alkali metal or alkaline earth metal hydroxideto form (VI); and hydrogenating (VI) to form(±)-3-(aminomethyl)-5-methylhexanoic acid (VII).

In a preferred embodiment of the present method,(±)-3-(aminomethyl)-5-methylhexanoic acid can be made by condensingisovaleraldehyde (I) with (II) to form (III); reacting (III) with acyanide source to form (IV); hydrolyzing and decarboxylating (IV) toform (VI); and hydrogenating (VI) to form(±)-3-(aminomethyl)-5-methylhexanoic acid (VII).

Also provided by the present invention is a method for obtaining(S)-3-(aminomethyl)-5-methylhexanoic acid (IX) from (±) -3-(aminomethyl) -5-methylhexanoic acid (VII), the method comprisingcombining (±)-3-(aminomethyl)-5-methylhexanoic acid and (S)-mandelicacid in water, an alcohol or a mixture of water and an alcohol; allowinga precipitate to form; introducing the precipitate into a polar aproticsolvent, or a polar aprotic solvent and water, to form a slurry; andcollecting the solid from the slurry.

In one step of the present method for making(±)-3-(aminomethyl)-5-methylhexanoic acid, isovaleraldehyde is condensedwith ##STR30## wherein R₁ and R₂ are the same or different and arehydrogen C₁ -C₆ alkyl, aryl, benzyl, or C₃ -C₆ cycloalkyl. This type ofreaction is known to those skilled in the art as a KnoevenagelCondensation, and the conditions under which a Knoevenagel Condensationcan be carried out are well known to those skilled in the art. Forexample, the condensation can be achieved using a catalytic amount of abase such as di-n-propylamine. Other suitable catalysts are known in theliterature. See for example, Tietze L. F., and Beifuss U. inComprehensive Organic Synthesis, 199172:341-394 (Trost B. M., ed.),Pergamon Press. Representative examples of suitable catalysts includepyrrolidine, β-alanine, ammonium acetate, di-isoproplylamine, anddi-n-propylamine. These basic catalysts can also be used in combinationwith an acid such as p-toluene sulfonic acid or acetic acid. A preferredcatalyst system in the present method is di-n-propylamine and aceticacid.

In general, the reaction is run in a refluxing hydrocarbon solventincluding, but not limited to, toluene, hexane, heptane, methyltert-butyl ether or cyclohexane, with the azeotropic removal of water. Apreferred solvent is hexane. It is noted that olefin regioisomers canalso be formed in the reaction, but are converted to the desired productin a subsequent step in the reaction sequence.

Representative examples of C₁ -C₆ alkyl groups include methyl, ethyl,propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl and hexyl.Representative examples of C₃ -C₆ cycloalkyl include cyclopropyl,cyclobutyl, cyclopentyl and cyclohexyl. Representative examples of arylgroups include phenyl and substituted phenyl, naphthyl, pridinyl, andthe like. The aryl moiety my be substituted with one or moresubstituents, which can be the same or different. Examples of suchgroups include C₁ -C₆ alkyl, C₁ -C₆ alkoxy and halogen. Preferably, R₁and R₂ are ethyl. In general, the isovaleraldehyde and ##STR31## areadded to the solvent along with the catalyst, and refluxed withazeotropic removal of water. It is also contemplated that additionalcatalyst my be added when the rate of azeotropic water collection slows.The progress of the condensation reaction my be monitored by methodswell known in the art. A preferred monitoring method is gaschromatography (GC).

In another step of the present method, ##STR32## is reacted with acyanide source to form ##STR33## In general, ##STR34## is reacted with acyanide source in a polar protic solvent such as ethanol, methanol,n-propanol, isopropanol, a mixture of water and alcohols, or polaraprotic solvents such as dimethylsulfoxide (DMSO) or DMSO/water, andthen treated with an acid. Examples of suitable cyanide sources include,but are not limited to, hydrogen cyanide, acetone cyanohydrin or analkali metal or alkaline earth metal cyanide, such as sodium cyanide,potassium cyanide, or magnesium cyanide. The ##STR35## in this step maybe used in the next step without purification, i.e. in crude form, or itmay be purified. Examples of suitable acids are acetic acid,hydrochloric acid, hydrobromic acid, sulfuric acid, benzoic acid,mandelic acid, p-toluenesulfonic acid, and the like.

The ##STR36## can be decarboxylated to form ##STR37## by heating##STR38## in a solvent with a salt. Examples of suitable solventsinclude mixtures of water and a polar solvent such as ethanol ordimethylsulfoxide (DMSO). Examples of suitable salts include alkalimetal and alkaline earth metal halides such as sodium chloride andalkali metal and alkaline earth metal cyanides such as sodium cyanide,magnesium cyanide, and the like.

The ##STR39## can be hydrolyzed with an alkali metal hydroxide or analkaline earth metal hydroxide to form an alkali or alkaline earth metalcarboxylate salt. The alkali or alkaline earth metal hydroxide can beany alkali or alkaline earth metal hydroxide known to those skilled inthe art. Examples of suitable alkali metal hydroxides include sodiumhydroxide, lithium hydroxide, and potassium hydroxide. Examples ofsuitable alkaline earth metal hydroxides include calcium hydroxide andmagnesium hydroxide. The reaction is usually run in a suitable proticsolvent such as water or a mixture of water and a polar protic solventsuch as methanol, ethanol, or isopropanol.

The carboxylate salt can be reduced to give the alkali or alkaline earthmetal salt of (±)-3-(aminomethyl)-5-methylhexanoic acid. The carboxylatesalt can be protonated with mineral acids or carboxylic acids to givethe carboxylic acid and then the nitrile group of the carboxylic acidcan be reduced. Conversely, the nitrile group of the carboxylate saltcan be reduced, and subsequently protonated to form the carboxylic acid.The salt can be treated with mineral acids or carboxylic acids to give(±)-3-(aminomethyl)-5-methylhexanoic acid. Those skilled in the art arefamiliar with the reduction of nitrile functional groups. One commonmethod of reducing a nitrile uses a hydrogenation catalyst, such assponge nickel, in the presence of hydrogen. Other catalysts includepalladium, platium, rhodium, cobalt, and nickel. In general, thereaction is run in a solvent system such as a mixture of water and apolar protic solvent.

The amino carboxylate formed after nitrile reduction can be obtained inthe acid form by treating the amino carboxylate with an acid. Themineral acids such as hydrochloric acid can be used. Carboxylic acids,such as acetic acid, can also be used. Preferably, the acid is aceticacid, as a byproduct formed by the reaction is MOAc where M is an alkalimetal ion (Na, K, and the like), and OAc is an acetate ion. The saltMOAc is more soluble in aqueous alcoholic solvents than inorganic saltssuch as sodium chloride, potassium chloride, and the like. Thus,isolation of the product is simplified, and the need for ion exchangetreatment to remove excess salts is avoided.

The cyano acid may also be reduced using a suitable hydrogenationcatalyst, such as sponge nickel and hydrogen, in a polar solvent such asmethanol, ethanol, or isopropanol in combination with ammonia or amixture of ammonia and water. Examples of other suitable hydrogenationcatalysts include palladium, platium, rhodium, cobalt, and nickel.

In a preferred method ##STR40## is taken to(±)-3-(aminomethyl)-5-methylhexanoic acid without isolation ofintermediates. For example, ##STR41## can be hydrolyzed using an alkalior alkaline earth metal hydroxide such as potassium hydroxide or sodiumhydroxide in an alcohol solvent, which promotes decarboxylation. Furtherhydrolysis using an alkali or alkaline earth metal hydroxide in water,an alcohol, or a mixture of water and an alcohol, gives carboxylate(VI), which can be reduced with a hydrogenation catalyst followed bytreatment with a mineral acid to give racemic3-(aminomethyl)-5-methylhexanoic acid.

Racemic 3-(aminomethyl)-5-methylhexanoic acid can be resolved, i.e., theenantiomers separated, by selective crystallization with (S)-mandelicacid. Racemic 3-(aminomethyl)-5-methylhexanoic acid and (S)-mandelicacid can be combined in a solvent such as water or an alcohol or amixture of water and an alcohol to form a salt. Examples of suitablealcohols include methanol, ethanol, n-propanol, isopropanol, n-butanol,tert-butanol, and the like. In general, the S,S salt precipitates fromthe solution, and the diastereomer, the R,S salt, stays in solution.Diasteriomeric purity of the S,S salt can be enhanced by furthercrystallizations. Additional (S)-mandelic acid can be included in therecrystallizations to enhance diastereomeric enrichment. In general, anexcess of mandelic acid is used. It is also noted that mandelic acid canbe used in combination with another acid in accordance with the"Pope-Peachy" method known in the art.

Removal of (S)-mandelic acid from the salt to give enriched(S)-3-(aminomethyl)-5-methylhexanoic acid can be done using a polaraprotic solvent such as dimethylsulfoxide or mixtures ofdimethylsulfoxide and water or tetrahydrofuran and water, attemperatures typically in the range of about 0° C. to about 100° C.

Trituration to obtain the S-enantiomer has the advantage that it isoperationally simple and more economical than traditional acid/base orion exchange methods.

Alternatively, (S)-3-(aminomethyl)-5-methyl-hexanoic acid can beobtained by combining (±)-3-(aminomethyl)-5-methylhexanoic acid with(R)-mandelic acid to give the R,R salt which crystallizes out of thesolution leaving the solution enriched in(S)-3-(aminomethyl)-5-methylhexanoic acid which can then be isolatedfrom the solution by methods well known to those skilled in the art.

The (R)-mandelic salt of (S)-3-(aminomethyl)-5-methylhexanoic acid canbe isolated as an intermediate, treated with a polar aprotic solvent ormixture of water and a polar aprotic solvent to give the(S)-3-(aminomethyl)-5-methylhexanoic acid.

It is also possible to obtain (S)-3-(amino methyl)-5-methylhexanoic acidfrom racemic isobutyl-GABA by standard methods of resolution known tothose skilled in the art. It is noted that the isolated solids may bedried at each stage in the resolution or carried on to the next step assolvent-wet solids with comparable results.

Also provided by the present invention are the novel compounds ##STR42##where R₁ and R₂ are the same or different and are hydrogen, C₁ -C₆alkyl, aryl, benzyl or C₃ -C₆ cycloalkyl; ##STR43## where M is hydrogen,an alkali metal, or an alkaline earth metal; ##STR44## where R₁ is adefined above; and ##STR45##

It is also contemplated that the compounds of the present method can befound or isolated in the form of hydrates or solvates, which areconsidered to fall within the scope of the present invention.

The examples below are intended to illustrate specific embodiments ofthe invention and are not intended to limit the scope of thespecification, including the claims, in any manner.

EXAMPLES Preparation of 2-Carboxyethyl-5-methylhex-2-enoic acid, ethylester ##STR46##

Isovaleraldehyde (361.6 kg, 4198.3 mol) was combined with diethylmalonate (640.8 kg, 4000.7 mol), hexane (1000 L), di-n-propylamine (20.0kg, 197.6 mol), and glacial acetic acid (24.0 kg, 399.7 mol) in a 4000 Lvessel. The mixture was heated to reflux (jacket temperature set at 90°C.) with continuous removal of water until the rate of water collectionslowed significantly (69.4 kg water was collected versus 72.0 kgexpected by theory).

At this point, the mixture was cooled to below 60° C. and a secondcatalyst addition was carried out by charging di-n-propylamine (20.0 kg,197.6 mol), and glacial acetic acid (24.0 kg, 399.7 mol) to the mixture.(The second catalyst addition is optional, but helps to bring thereaction to completion faster. This modification shows improved purityprofiles and yields in some cases versus a single catalyst charge.)

The mixture was heated to reflux (jacket temperature set at 90° C.) withcontinuous removal of water for an additional 22.5 hours or until thereaction is judged complete by GC assay (>90% combined product andisomer). The mixture was brought to <40° C. and was washed with water(2×800 L). The organic layer was concentrated by atmospheric pressuredistillation until most of the hexane was removed. The remaining oil wasfurther concentrated by vacuum distillation at 40° C. for 2-18 hours.

The product was obtained as a colorless liquid (810.0 kg, 88.7% yield)and contained a mixture of olefin isomers (both of which are convertedto the same product in the next synthetic step). The major isomer is2-carboxyethyl-5-methylhex-2-enoic acid, ethyl ester; the minor isomer(typically 10-13% by GC) is believed to be2-carboxyethyl-5-methylhex-3-enoic acid, ethyl ester.

Description: Colorless to yellow liquid

GC Assay: 74-76% 2-carboxyethyl-5-methylhex-2-enoic acid ethyl ester;10-13% 2-carboxyethyl-5-methylhex-3-enoic acid ethyl ester; 87-88% Totalof both isomers.

¹ H NMR, Note: Chemical shifts and multiplicities are reported asobserved for a sample of the mixture prepared by the process describedabove. The observed integration results are slightly different thanwould be expected for pure 2-carboxyethyl-5-methylhex-2-enoic acid ethylester due to the presence of two olefin isomers. Thus, the integrationhas been reported as would be expected for a pure sample of2-carboxyethyl-5-methylhex-2-enoic acid ethyl ester.

¹ H NMR (CDCl₃, 200 MHz): δ 0.91-1.02 (m, 6H) , 1.23-1.37 (m, 6H),1.78-1.85 (m, 1H), 2.16-2.23 (m, 2H) 4.19-4.36 (m, 4H), 7.02 (t, 1H,J=7.9 Hz).

Boiling Point: Purified samples can be obtained by vacuum distillation:101°-104° C. at 1.1-1.2 mm Hg; or 132° C. at 5 mm Hg.

Preparation of 2-Carboxyethyl-3-cyano-5-methylhexanoic acid, ethyl ester##STR47##

2-Carboxyethyl-5-methylhex-2-enoic acid ethyl ester (692.7 kg, 3034 mol)was charged to a 4000 L vessel containing potassium cyanide (172.6 kg,2650 mol) and 2B ethanol (700 kg). The resulting slurry was stirred at25°-40° C. for at least 18 hours or until in-process HPLC assayindicated less than 5% 2-carboxyethyl-5-methylhex-2-enoic acid, ethylester (typically 22-24 hours). Hexane (890 L) was charged to the slurry.Glacial acetic acid (175 kg, 2914 mol) was slowly added keeping thetemperature <35° C. To the resulting thick slurry was added water (820L) with stirring. The layers were separated. The aqueous layer wasextracted with hexane (1×890 L). The organic layers were combined andwashed with water (1×420 L). The water layer was separated and theremaining organic solution was distilled at atmospheric pressure untilmost of the hexane was removed. The oil was then further concentrated byvacuum distillation at 40° C. for 2-19 hours. The product was obtainedas a liquid (752.6 kg, 93.8%).

Description: Colorless to orange liquid

HPLC Assay: 83-86% 2-carboxyethyl-3-cyano-5-methylhexanoic acid, ethylester

¹ H NMR (DMSO-d₆, 200 MHz): δ 0.92 (t, 6H, J=6.1 Hz), 1.15-1.21 (m, 6H),1.23-1.36 (m, 1H), 1.54-1.68 (m, 2H), 3.25-3.33 (m, 1H), 3.97 (d, 1H,J=6.5 Hz), 4.10-4.25 (m, 4H).

Preparation of 3-Cyano-5-methylhexanoic acid, ethyl ester ##STR48##

An 800 L still was charged with sodium chloride (21 kg, 359 mol),2-carboxyethyl-3-cyano-5-methylhexanoic acid, ethyl ester (80.0 kg, 313mol), dimethylsulfoxide (238 kg), and water (10.8 kg, 600 mol). Themixture was heated to 137°-148° C. for 8.5 hours. The mixture was cooledto below 50° C., and treated with methyl tert-butyl ether (125 kg). Themixture was cooled to 0°-10° C., and treated with water (160 L) inportions to maintain the temperature below 40° C. After stirring for15-30 minutes, the phases were separated. The aqueous phase wasextracted with methyl tert-butyl ether (125 kg). The organic extractswere combined with a vessel rinse (25 kg methyl tert-butyl ether) andwas extracted with water (110 L). The water phase was discarded. Themethyl tert-butyl ether phase was concentrated by atmospheric pressuredistillation to a batch temperature of about 65° C. The batch was cooledto 30°-40° C. and further concentrated by vacuum distillation until thesolvent content was acceptable (<5% methyl tert-butyl ether by area %GCanalysis). The product was obtained as a brown oil (51.3 kg, 85.7%).

Description: Colorless to dark brown oil

GC Assay (area %): 86.20%

Boiling Point: Purified samples can be obtained by vacuum distillation:99°-103° C. at 1.3-1.5 mm Hg

¹ H NMR (CDCl₃, 200 MHz): δ 0.88-0.99 (m, 6H), 1.19-1.40 (m, 4H),1.57-1.69 (m, 1H), 1.72-1.84 (m, 1H), 2.53 (dd, 1H, J=6.8 Hz, J=16.6Hz), 2.70 (dd, 1H, J=7.4 Hz, J=16.5 Hz), 2.99-3.10 (m, 1H), 4.21 (q, 2H,J=7.1 Hz).

Preparation of Racemic 3-(Aminomethyl)-5-methylhexanoic acid ##STR49##

An 800 L still was charged with 3-cyano-5-methyl hexanoic acid, ethylester (50.1 kg, 273 mol) and ethyl alcohol 2B (53 kg). A solution ofpotassium hydroxide (17.8 kg, 317 mol) in water (56 L) was addedcontrolling the addition rate to maintain the batch temperature below25° C. The mixture was stirred at 20°-25° C. for about 1.5 hours.

The batch was transferred to a hydrogenator containing sponge nickel(15.0 kg, 50% water wet), followed by a rinse of ethyl alcohol 2B (27kg). The mixture was treated with hydrogen at about 50 psi for about 19hours (hydrogen uptake stopped).

The nickel was removed by filtration and the filter cake was rinsed witha mixture of 39 kg ethyl alcohol 2B and 111 L water. To the filtrate wasadded glacial acetic acid (22.8 kg, 380 mol) maintaining the batchtemperature less than 40° C. The batch was heated to 70°-75° C. todissolve the solids. The batch was slowly cooled to 0°-5° C. tocrystallize the product.

The solid was collected on a centrifuge and rinsed with 160 L isopropylalcohol that was previously cooled to 0°-5° C.

The damp solid was dried in a vacuum tray drier under vacuum at 35°-45°C. (28 hours) to give 31.4 kg (75.1%) of racemic3-aminomethyl-5-methylhexanoic acid.

The product was characterized by HPLC and NMR. The water content forthis product was 9.51% by weight (Karl Fischer). The product may containa variable amount of water ranging from nearly anhydrous up to about10.2% (monohydrate).

Description: White to off-white solid

HPLC Assay: 102.05% w/w

Melting Point: 166.0°-167.5° C.

¹ H NMR (D₂ O, 200 MHz): δ 0.86-0.90 (m, 6H), 1.21 (t, 2H, J=7.0 Hz),1.62-1.69 (m, 1H), 2.12-2.35 (m, 3H), 2.94-3.00 (m, 2H).

Preparation of Racemic 3-(Aminomethyl)-5-methylhexanoic acid ##STR50##

A 2000 L still was charged with 2-carboxyethyl-3-cyano-5-methyl hexanoicacid, ethyl ester (286 kg, 1120 mol) and methyl alcohol (100 L). Asolution of potassium hydroxide (60.8 kg, 1046 mol) in methyl alcohol(260 L) was added controlling the addition rate so as to keep the batchtemperature about 20°-35° C. A rinse of 40 L methyl alcohol was added tothe batch and the mixture was heated to reflux for 4-5 hours. The batchwas cooled to 25°-30° C. and a solution of potassium hydroxide (121.6kg, 2167 mol) in water (200 L) was added maintaining the batchtemperature below 50° C.

The batch was concentrated by vacuum distillation to about 580 L volume.Water (100 L) was added and the distillation continued to a volume ofabout 510 L.

The batch was transferred to an 800 L hydrogenator containing 44.8 kgsponge nickel (50% water wet), along with a mixture of 20 L water and 30kg ethyl alcohol 2B as a rinse. The mixture was treated with hydrogen atabout 50 psi for about 18-19 hours (hydrogen uptake stopped).

To the batch was added 58 kg ethyl alcohol 2B and the nickel was removedby filtration. The filter cake was rinsed with a mixture of 100 kg ethylalcohol 2B and 270 L water.

The filtrate was transferred to a 2000 L still containing 222 kg (3697mol) glacial acetic acid at 50°-60° C. controlling the addition rate tocontrol gas evolution and to maintain the temperature at 50°-60° C. Arinse of 40 L water was added to the batch and the temperature increasedto 70°-75° C. to dissolve the solids. The batch was slowly cooled to0°-5° C. to crystallize the product.

The solid was collected on a centrifuge and rinsed with 570 L isopropylalcohol.

The damp solid was dried in a vacuum tray drier under vacuum at 35°-45°C. (22 hours) to give 108.1 kg (72.7%) of racemic3-aminomethyl-5-methylhexanoic acid. The product was characterized byHPLC and NMR. The product may contain variable amounts of water rangingfrom nearly anhydrous (1.68% by weight in this example) up to about10.2% (monohydrate).

Description: White to off-white solid

HPLC Assay: 99.67% w/w

Melting Point: 166.0°-167.5° C.

¹ H NMR (D₂ O, 200 MHz): δ 0.88-0.92 (m, 6H) , 1.23 (t, 2H, J=6.9 Hz),1.64-1.70 (m, 1H), 2.13-2.37 (m, 3H), 2.96-3.01 (m, 2H).

Resolution of Racemic 3-(Aminomethyl)-5-methylhexanoic acid ##STR51##

A solution of 3% v/v water in isopropyl alcohol was prepared by mixingwater (9 kg) and isopropyl alcohol (291 L) in a 400 L reactor. This wasrepeated. The solvent was stored in plastic drums and used as necessary(described below).

A 400 L still was charged with racemic 3-aminomethyl-5-methylhexanoicacid (29.7 kg, 168 mol), S-(+)-mandelic acid (39.3 kg, 258 mol), and 3%v/v water/isopropyl alcohol solution (244 kg) prepared earlier. Themixture was heated to dissolve the solids (about 65°-80° C.), cooled,and seeded with S,S-salt to crystallize the mixture of diastereomericmandelate salts enriched in the S,S-isomer. The solid was collected on acentrifuge and rinsed with 3% water/isopropanol (21.5 kg). (S/R isomerratio: 93.7% S: 6.3% R. The solid may optionally be dried at this stageor carried on as a solvent-wet solid).

The damp salt was charged to a 400 L still along with (S)-(+)-mandelicacid (5.8 kg, 38 mol) and 3% water/isopropyl alcohol (121 kg). Themixture was heated to dissolve the solids (about 65°-80° C.), cooled,and seeded if necessary, with S,S-salt to crystallize the mixture ofdiastereomeric mandelate salts further enriched in the S,S-isomer. Thesolid was collected on a centrifuge and rinsed with 3% water/isopropylalcohol (33.3 kg). The solid may optionally be dried at this stage orcarried on as a solvent-wet solid (S/R isomer ratio: 99.5% S:0.5% R).The dried S,S-salt typically has the following characteristics:Description: White to off-white solid; mp 133°-134° C.;

¹ H NMR (D₂ O, 200 MHz): δ 0.87-0.92 (m, 6H) , 1.24 (t, J=7.2 Hz, 2H),1.55-1.76 (m, 1H), 2.11-2.52 (m, 3H), 3.00 (d, J=6.2 Hz, 2H), 5.07 (s,1H), 7.43 (s, 5H).

The damp salt was transferred to a 400 L reactor with tetrahydrofuran(195 L) and water (10 kg). The mixture was warmed to 60°-65° C., andcooled to 0°-5° C. The crude (S)-isobutyl GABA solid was collected on acentrifuge and rinsed with a mixture of tetrahydrofuran (28 L)/water (1kg). The solid may optionally be dried at this stage or carried on as asolvent-wet solid (S/R isomer ratio: 100% S:<0.05% R isomer (notdetected)).

The damp solid was transferred to a 200 L still with isopropyl alcohol(113 L) and water (38 kg). The mixture was heated to dissolve the solids(about 75°-80° C.), filtered while hot, and cooled to 0°-5° C. tocrystallize the (S)-isobutyl GABA. The solid was collected on acentrifuge and rinsed with 25 L isopropyl alcohol. The damp solid wasdried in a vacuum tray drier under vacuum at 35°-45° C. to give 7.4 kg(S)-isobutyl GABA.

Description: White to off-white solid

HPLC Assay: 99.4% w/w

Chiral Purity (HPLC): 100% S; R-isomer not detected (limit of detection0.05%)

Melting Point: 177°-179° C. (decomposes)

¹ H NMR (D₂ O, 200 MHz): δ 0.88-0.92 (m, 6H), 1.23 (t, 2H, J=6.9 Hz),1.64-1.70 (m, 1H), 2.13-2.32 (m, 3H), 2.96-3.01 (m, 2H).

Resolution of Racemic 3-(Aminomethyl)-5-methylhexanoic acid

A solution of 3% v/v water in isopropyl alcohol was prepared by mixingwater (5.7 kg) and isopropyl alcohol (184 L) in a 400 L reactor. Thesolvent was stored in plastic drums and used as necessary (describedbelow).

A 2000 L reactor was charged with racemic 3-aminomethyl-5-methylhexanoicacid (117.6 kg, 673 mol). A 2000 L still was charged with water (36 L),S-(+)-mandelic acid (153.0 kg, 1006 mol), and isopropyl alcohol (1170L). The mandelic acid mixture was heated to 55°-65° C. and the resultingsolution was transferred to the reactor containing racemic3-aminomethyl-5-methylhexanoic acid. The batch was heated to 50°-65° C.just long enough to dissolve the solids.

[Note: Batch heating and temperature are kept to the minimum necessaryto dissolve solids in order to minimize acid catalyzed decomposition ofracemic 3-aminomethyl-5-methylhexanoic acid to the corresponding lactam.This decomposition is undesired because it lowers product yield.]

The mixture was cooled to 40°-45° C., seeded with S,S-salt (20 g), andfurther cooled to 20°-25° C. to crystallize the mixture ofdiastereomeric mandelate salts enriched in the S,S-isomer. Aftermaintaining the temperature at 20°-25° C. for at least 12 hours, thesolid was collected on a centrifuge and rinsed with 3% water/isopropanolsolution (100 kg) prepared earlier.

[Note: S/R isomer ratio: 92.5% S:7.5% R. The solid may optionally bedried at this stage or carried on as a solvent-wet solid.]

The solvent-wet S,S-salt was charged to an 800 L reactor. An 800 L stillwas charged with water (14.4 kg), (S)-(+)-mandelic acid (23.0 kg, 151mol), and isopropyl alcohol (468 L). The mandelic acid mixture washeated to 65°-70° C., and the resulting solution was transferred to thereactor containing the solvent-wet salt. The batch was heated to 60°-70°C. just long enough to dissolve the solids or, if solids do notdissolve, until batch temperature reached 70° C.

[Note: Batch heating and temperature are kept to the minimum necessaryeither to dissolve solids or to reach 70° C., in order to minimize acidcatalyzed decomposition to the corresponding lactam. This decompositionis undesired because it lowers product yield.]

The mixture was cooled to 50°-55° C. Seeding with S,S-salt at thistemperature range is optional but is typically not needed to inducecrystallization or further diastereomeric enrichment. The batch wasfurther cooled to 0°-5° C. to crystallize the mixture of diastereomericmandelate salts enriched in the S,S-isomer. After maintaining thetemperature at 0°-5° C. for at least 12 hours, the solid was collectedon a centrifuge and rinsed with 3% water/isopropanol solution (100 kg)prepared earlier.

[Note: S/R isomer ratio: 98.6% S:1.4% R. The solid may optionally bedried at this stage or carried on as a solvent-wet solid. The driedS,S-salt typically has the following characteristics:

Description: White to off-white solid; mp 133°-134° C. [36832×88]; ¹ HNMR (D₂ O, 200 MHz): δ 0.87-0.92 (m, 6H), 1.24 (t, J=7.2 Hz, 2H),1.55-1.76 (m, 1H), 2.11-2.52 (m, 3H), 3.00 (d, J=6.2 Hz, 2H), 5.07 (s,1H), 7.43 (s, 5H).]

An 800 L reactor was charged with water (31 L), the solvent-wetS,S-salt, and tetrahydrofuran (595 L). The mixture was warmed to 50°-55°C., and cooled to 0°-5° C. After maintaining the temperature at 0°-5° C.for at least 12 hours, the solid was collected on a centrifuge andrinsed with tetrahydrofuran (50 L) and then with isopropyl alcohol (50L).

[Note: S/R isomer ratio: 99.94% S:0.06% R. The solid may optionally bedried at this stage or carried on as a solvent-wet solid.]

An 800 L reactor was charged with water (155 L), the solvent-wetCI-1008, and isopropyl alcohol (465 L). The mixture was heated todissolve the solids (about 75°-80° C.), filtered while hot, cooled to40°-45° C., seeded with CI-1008 (10 g), and further cooled to 0° C. to-5° C. to crystallize the CI-1008. The solid was collected on acentrifuge and rinsed with isopropyl alcohol (50 L). The damp solid wasdried in a vacuum tray drier under vacuum at 35°-45° C. to give 32.4 kgCI-1008 (60.4% yield).

Description: White to off-white solid

HPLC Assay: 100.32% w/w

Chiral Purity (HPLC): 100% S; R-isomer not detected (limit of detection0.05%)

¹ H NMR (D₂ O, 200 MHz): δ 0.86-0.90 (m, 6H), 1.21 (t, 2H, J=7.1 Hz),1.62-1.65 (m, 1H), 2.15-2.35 (m, 3H), 2.94-2.99 (m, 2H). [CD 2586]

Melting Point: 177°-179° C. (decomposes)

We claim:
 1. A method for obtaining (S)-3-(aminomethyl)-5-methylhexanoicacid from (±)-3-(aminomethyl)-5-methylhexanoic acid, the methodcomprising:a. combining (±)-3-(aminomethyl)-5-methylhexanoic acid and(S)-mandelic acid in water, an alcohol, or a mixture of water and analcohol; b. allowing a precipitate to form; c. introducing theprecipitate into a polar aprotic solvent or a mixture of polar aproticsolvent and water to form a slurry; and d. collecting the solid from theslurry.
 2. The method of claim 1 wherein the(±)-3-(aminomethyl)-5-methylhexanoic acid and (S)-mandelic acid arecombined in a 3% v/v solution of water in isopropyl alcohol.
 3. Themethod of claim 10 wherein the (±)-3-(aminomethyl)-5-methylhexanoic acidand (S)-mandelic acid are combined in methanol and isopropanol.
 4. Themethod of claim 1 wherein the polar aprotic solvent isdimethylsulfoxide.
 5. The method of claim 1 wherein the polar aproticsolvent is tetrahydrofuran.
 6. A method of making(±)-3-(aminomethyl)-5-methylhexanoic acid, the method comprising:a.condensing isovaleraldehyde with ##STR52## to form primarily ##STR53##b. reacting the ##STR54## with a cyanide source to form ##STR55## c.decarboxylating the ##STR56## to form ##STR57## d. hydrolyzing the##STR58## with an alkali or alkaline earth metal hydroxide to form analkali or alkaline earth metal carboxylate salt; and e. hydrogenatingthe alkali or alkaline earth metal carboxylate salt to form(±)-3-(aminomethyl)-5-methylhexanoic acid, wherein R₁ and R₂ are thesame or different and are hydrogen, C₁ -C₆ alkyl, aryl, benzyl, or C₃-C₆ cycloalkyl.
 7. The method of claim 30 wherein R₁ and R₂ of ##STR59##are ethyl.
 8. The method of claim 6 wherein the isovaleraldehyde and##STR60## are condensed in the presence of di-n-propylamine and aceticacid.
 9. The method of claim 6 wherein the cyanide source is potassiumcyanide.
 10. The method of claim 6 wherein the alkali metal hydroxide ispotassium hydroxide.
 11. The method of claim 6 wherein the hydrogenationis carried out in the presence of hydrogen and sponge nickel.
 12. Themethod of claim 6 which further comprises the step of resolving the(±)-3-(aminomethyl)-5-methylhexanoic acid to obtain(S)-3-(aminomethyl)-5-methylhexanoic acid.
 13. The method of claim 12wherein the resolution step comprises:a. combining(±)-3-(aminomethyl)-5-methylhexanoic acid and (S)-mandelic acid inwater, an alcohol, or a mixture of water and an alcohol; b. allowing aprecipitate to form; c. introducing the precipitate into a polar aproticsolvent or a mixture of polar aprotic solvent and water to form aslurry; and d. collecting the solid from the slurry.
 14. A method ofmaking (±)-3-(aminomethyl)-5-methylhexanoic acid, the methodcomprising:a. condensing isovaleraldehyde with ##STR61## to formprimarily ##STR62## b. reacting the ##STR63## with a cyanide source toform ##STR64## c. decarboxylating the ##STR65## to form an alkali oralkaline earth metal carboxylate salt; and d. hydrogenating the alkalior alkaline earth metal carboxylate salt to form(±)-3-(aminomethyl)-5-methylhexanoic acid.
 15. The method of claim 14wherein R₁ and R₂ of ##STR66## are ethyl.
 16. The method of claim 14wherein the isovaleraldehyde and ##STR67## are condensed in the presenceof di-n-propylamine and acetic acid.
 17. The method of claim 14 whereinthe cyanide compound is potassium cyanide.
 18. The method of claim 14wherein the hydrogenation is carried out in the presence of hydrogen andsponge nickel.
 19. The method of claim 14 which further comprises thestep of resolving the (±)-3-(aminomethyl)-5-methylhexanoic acid toobtain (S)-3-(aminomethyl)-5-methylhexanoic acid.
 20. The method ofclaim 19 wherein the resolution step comprises:a. combining(±)-3-(aminomethyl)-5-methylhexanoic acid and (S)-mandelic acid inwater, an alcohol, or a mixture of water and an alcohol; b. allowing aprecipitate to form; c. introducing the precipitate into a polar aproticsolvent or a mixture of polar aprotic solvent and water to form aslurry; and d. collecting the solid from the slurry.